Iontophoretic treatment system

ABSTRACT

A method and apparatus for applying iontophoretic treatment to a biological subject wherein electrical treatment current between a pair of electrodes is periodically reversed at very low frequencies, substantially in the range of approximately 0.0027 Hz to approximately 10 Hz, to mitigate tissue damage, enable long term dosimetry with single and multiple drugs of any polarity and at higher concentrations, and eliminate the need for buffering agents and the like, all in a relatively simple, economical and compact physical packaging configuration. The system delivers treatment substances with large and/or small molecular size and weight and can be adjusted to control pH at the delivery site. A method of lowering resistance and enhancing permeability at the delivery site, as well as increasing drug concentrations and delivery rates.

This application is a continuation of U.S. continuation patentapplication Ser. No. 08/558,510 filed Nov. 16, 1995 pending, which is acontinuation patent application Ser. No. 08/355,097 filed Dec. 13, 1994now abandoned, which is a continuation patent application Ser. No.08/128,320 filed Sep. 29, 1993 now abandoned, which is a continuation ofpatent application Ser. No. 07/995,349 filed Dec. 22, 1992 nowabandoned, which is a continuation patent application Ser. No.07/776,766 filed Oct. 15, 1991 now abandoned, which is acontinuation-in-part of patent application Ser. No. 07/607,874 filedNov. 1, 1990 now U.S. Pat. No. 5,224,927 issued Jul. 6, 1993.

BACKGROUND OF THE INVENTION

This invention relates generally to improvements in methods andapparatus for effecting an electrotherapeutic treatment on a biologicalsubject, such as iontophoretic delivery of medicaments and, moreparticularly, to a new and improved system for the application of aniontophoretic treatment topically to the skin of a human body.

Around the turn of the century there was disclosed a plethora ofelectrode types for applying “electric treatments” to the human body.The electrodes were normally placed upon the body in relation to theposition of the organ to be treated. Such “electric treatments”encompassed a wide range of applications. For example, galvanic (directcurrent) treatments have been popular in the past for their polareffects on ionized molecules, causing the ionized molecules to be driventhrough the skin, usually superficially. This phenomenon is known asiontophoresis or ion transfer, and it has been employed for theintroduction of medicaments or even simply moisture, into the skin of apatient.

More specifically, and by way of example, some ions of zinc and coppercan be employed in the treatment of various skin infections, andchlorine ions have been employed for the loosening of superficial scars.Further, vasodilating drugs can be used in rheumatic and peripheralvascular affections, and skin anesthesia can be produced byiontophoresis of local anesthetic drugs. Moreover, iontophoreticadministration of drugs typically avoids the gastrointestinal sideeffects sometimes associated with direct ingestion of such drugs.

Although the aforementioned iontophoretic treatments have been found tobe effective, they are also known to be accompanied by a number ofundesirable side effects, such as the occurrence of skin injury in theform of iontophoretic burns and irritation in the treated area, as wellas the formation of undesirable vesicles and bulla, on the skin in thetreated area. Various complicated or compromised methods for preventingthese iontophoretic burns have been developed. However, such methods andapparatus have generally been found not to be adequately effective forpreventing irritation and the formation of vesicles or bulla on the skinin the treated area. Consequently, iontophoretic treatments have usuallybeen limited to relatively low electrical currents and relatively shortperiods of administration of, typically, twenty, minutes or less.

Iontophoretic drug delivery systems of the prior art have also beenprimarily limited to delivering a drug of only a single polarity at atime to a given area, at relatively low concentrations, and have notbeen suitable for simultaneous delivery of multiple drugs. Furthermore,there were virtually no satisfactory iontophoretic devices which wererelatively simple, economical, compact, portable and capable of safe,long term delivery over several days, once applied to the patient andplaced into operation. Attempts to meet these needs have involved rathercomplex buffering, electrical or other compensatory systems which havenot proven entirely practical or satisfactory.

In addition to the foregoing difficulties, iontophoretic systems of thepast have not proven effective in the administration of drugs embodyingrelatively large and/or heavy molecular structures. Moreover, drugformulations intended for iontophoretic therapeutic drug delivery haveoftentimes required buffering agents for pH control. Control of pH atthe delivery site of the therapeutic drug has been essentially unknown.Furthermore, difficulties in obtaining sufficiently high rates ofinfusion, due to relatively high electrical resistance and/or poorpermeability at the delivery site, have also been encountered withiontophoretic systems.

The aforementioned difficulties and undesirable side effects ofiontophoretic treatment have resulted in a sometimes less thanenthusiastic reception of iontophoretic techniques by the medicalcommunity, in spite of the potentially great and varied advantages to berealized through their use and development.

Hence, those concerned with development and use of iontophoretic systemsin the medical field have long recognized the need for a convenient andeffective apparatus and method for preventing burns, irritation and theformation of vesicles and bulla on the skin in an area subjected to aniontophoretic treatment over extended periods of continuous treatment,for systems which can be physically packaged in a relatively simple,economical and compact configuration, can deliver therapeutic drugs at arelatively high rate and at higher concentrations, without the need forbuffering agents and the like, which are capable of delivering largemolecular substances such as insulin and the like, can deliver aplurality of drugs simultaneously in a relatively simple manner withoutmatching drug polarity, can be used to lower resistance and increasepermeability, and can be used to reliably control pH at the drugadministration site. As will become apparent from the ensuingdiscussion, the present invention clearly fulfills all of these needsand more.

SUMMARY OF THE INVENTION

Briefly, and in general terms, the present invention provides a methodand apparatus for applying electrical energy topically to a suitablesurface of a biological subject, such as the skin of a human body,particularly for the long term administration of medicaments and thelike or for other electrotherapeutic treatment, and by which theaforementioned deficiencies and undesired side effects are greatlyminimized and may be eliminated. Moreover, the system of the presentinvention is relatively inexpensive to manufacture, can be physicallypackaged in a completely self-contained, relatively simple and compactconfiguration, trouble free and reliable in use, is capable of higherdrug administration rates and drug concentrations, can deliver multipledrugs simultaneously in a simple manner, can control pH at the deliverysite, is capable of delivering large and/or heavy molecule drugs, is amore effective bactericidal, and is arranged to be safely, simply andreliably operated for self-treatment by an average person in normal homeuse, even for extended periods of several days at a time. Furthermore,it is contemplated in the practice of the invention that electricalimpedance at the administration site on the patient can be substantiallyreduced to vastly improve permeability and penetration and therebyfurther enhance medicament delivery.

Basically, the present invention is directed to a new and improvedsystem for iontophoretic drug administration which includes conductingdirect electrical current through the skin of a body, and periodicallyreversing the electrical current and conducting the current through theskin in the opposite direction, to effectively deliver very lowfrequency AC current, substantially in the critical range ofapproximately 0.0027 Hz to 10 Hz. It has been discovered that, withinthis substantially critical frequency window between approximately sixminutes per full cycle and approximately ten cycles per second, adramatic cancellation of skin damaging ions takes place. At frequencieshigher than approximately 10 Hz, no substantial effective delivery takesplace. At frequencies lower than approximately 0.0027 Hz, the risk ofskin injury increases substantially.

It is well known that the positive iontophoretic electrode, in additionto its primary function of driving like polarity ionic substances intothe skin of a subject, unfortunately produces skin damaging hydrochloricacid as well. Likewise, the negative iontophoretic electrode, inaddition to its primary function of driving like polarity ionicsubstances into the skin, unfortunately also produces skin damagingsodium hydroxide. However, within the aforestated frequency range of thepresent invention, either driving polarity delivers the desired ionictherapeutic substances, but also cancels the undesired skin damagingions with the reverse portion of the electrical cycle. The reason forneutralization of the harsh injury producing chemicals, i.e.,hydrochloric acid and sodium hydroxide, is that both of these chemicalsrequire a finite period of time on the skin to cause damage. Hence,these damaging chemicals are made to cancel each other before damagetakes place, by critical frequency selection, in accordance with theinvention, of the AC driving signal. Therefore, optimization of a longsought therapeutic device with reduced side effects has been achieved.

In accordance with the invention, electronic circuitry is provided toautomatically impose the reversal of electrical current at regularlyrepeating intervals of time, in accordance with the aforedescribedsubstantially critical frequency range, and the system can be adjustedto conduct the iontophoretic treatment at any desired level ofelectrical current.

More specifically, the present invention is directed to a novel conceptin overcoming the unwanted ions generated at the negative and positiveelectrodes of an iontophoretic drug delivery system, that lead to skindamage among other undesirable effects during iontophoresis. Inattempting to replicate the drug delivery capability of an IV unit thatwould be used continuously over days, iontophoretic devices of the pastare generally unsatisfactory because of their impracticality, complexityand/or the substantial skin damage they would cause. When the demand isfor use over days, the new, simplified and improved technology of thepresent invention is required to overcome the skin damaging acid andalkali generated at the electrodes. This new technology that results inthe hydrochloric acid and the sodium hydroxide canceling each other, wasachieved with the aforementioned extremely low frequency alternatingelectrical current that mimics the drug delivery of a direct currentsystem because it is so slow, but deposits otherwise harmful ions on thesame skin area to offset or neutralize each other before skin damage cantake place.

In accordance with the invention, a basic AC generator delivers a druginto the skin of a patient, but neutralizes opposing harmful chemicalsthat are inherently developed at the output electrodes when in anaqueous solution or gel form in contact with the skin during electricalcurrent flow. It has been discovered that, when the electrical currentis reversed at the slow rate of approximately 0.0027 Hz to 10 Hz, thebehavior of the drug is to react as if it were a DC signal in that thepolarity at any given moment will drive a like polarity drug componentinto the skin. The benefit achieved is that the unwanted chemical thatwas generated at the electrode was neutralized when the signal polarityreversed and developed an opposing chemical to cancel each other at theskin interface.

This non-invasive, minimal side effects system, in accordance with theinvention, is designed to deliver drugs either systemically, locally orboth, and is also appropriate for other iontophoretic treatment, such assweat inhibition and the like. It can be made in two or more forms,i.e., a long lasting iontophoretic patch with self-containedelectronics, or a larger unit that contains an electronics package forpower and control and which terminates into output jacks. The user thenplugs an electrical extension cable into these jacks and applies theother end of the cable, which terminates in a remote applicator housingsuitable iontophoretic electrodes and drug reservoirs, to the patient.This larger, more powerful unit is generally intended for shorter termuse. Large units, employing the frequency range of the presentinvention, may also be used for treating areas such as the foot whichmay soak in a liquid surfactant combined with an antifungal agent or thelike.

Previous DC iontophoretic devices necessarily required an “inactive” orground return electrode to electrically complete the circuit. Often,this electrode was remotely connected (“distal” electrode) adding to anunwieldy, space devouring component. Even if the inactive electrode wereadjacent to the active, drug driving electrode, it normally occupied atleast fifty percent of the space of the device for its simple, onedimensional purpose—to complete an electrical circuit. With the ACsystem of the present invention, the so-called “inactive” electrode ismade active, in that it contributes to driving the drug into the skinwhen its alternating polarity changes to be the same polarity of thetherapeutic medicament. Hence, both electrodes are used to infusetherapeutic drugs into the patient. This has another advantage from thepractitioner's view. The polarity of the drug need no longer be known inorder to place it in the correct polarity drug reservoir, since thepolarity of each reservoir reverses regularly. Otherwise an error couldbe made. The practitioner also need not stock applicators with twodifferent capabilities—one for positive and one for negative. In effect,the applicator size is doubled because of the presence of the AC signalin accordance with the invention.

The system of the present invention also uses relatively inexpensivesilicone/carbon electrodes. While this material is in common use withTENS devices (Transcutaneous Electrical Nerve Stimulators), it is notused for both electrodes for common DC iontophoretic devices. This isbecause these non-metallic electrodes typically show a high resistanceafter short use, with a consequent substantial drop in load current(especially the positive electrode). With a slow AC signal, it has beendiscovered that this build-up of resistance does not take place and bothelectrodes maintain the desired low electrical resistance. Thealternative to these low cost electrodes would be pure and extremelyexpensive palladium, platinum or rhodium electrodes to minimizecorrosion, but with the consequent possibility of metal ions beingdriven into the skin and further adding to “clutter”.

The presence of hydrochloric acid and sodium hydroxide does have abeneficial value in that these chemicals have a bactericidal effect.Each of these chemicals kill different groups of bacteria. In theconventional DC device, only one chemical is present at one electrodeand, therefore, attacks only a particular group of microbes. With an ACsignal, in accordance with the present invention, the antibacterialeffect takes place against the groups of microbes effected by bothpolarities and, within the substantially critical frequency range of theinvention, also avoids damage to the skin.

Heretofore, it was commonly accepted that drugs delivered byiontophoretic systems necessarily had to be limited to approximately oneto two percent concentration. Increasing the concentration of the drugnot only would not show an increase in drug concentration in the skin,but could actually decrease the amount of drug delivered because of“clutter” and competition to enter a very minute passageway (the eccrineduct). With the slow AC signal of the present invention, drugconcentration can now be increased substantially beyond two percent withvery important benefits that include enhanced therapeutic value andshortened treatment time.

The reason that the slow AC signal facilitates increased drug dosage orconcentration above two percent is as follows: If, for instance, apositively charged drug was in the drug reservoir when the positive halfof the AC signal was driving that same reservoir, then the positivecomponent of the drug would be repelled and driven into the skin. Sinceall drug molecules also contain a negative component that, in thisinstance, would be left behind in the reservoir (in a DC device) asnon-productive “clutter”, when the AC signal swings negative on theother half of the signal, the negative component also will be driven tothe skin, thereby eliminating the aforedescribed “clutter” from thereservoir. This “cleansing” of the area, by removal of otherwisedelivery inhibiting clutter, enables increased drug concentrations.

A further feature of the present invention resides in the ability todeliver drugs embodying large and/or heavy molecular structures, such asinsulin, since the frequency of operation of the system of the presentinvention both removes “clutter” as a drug transfer impediment and alsoprovides adequate molecular transport times.

In a presently preferred embodiment, the control signal generated by thesystem of the present invention is usually equal and opposite in allrespects so that opposing unwanted chemicals cancel each other andmaintain a neutral pH of approximately 7. The electrical circuitry mayalso be modified to favor the positive portion of the electrical cycle,rather than being exactly the same amplitude as the negative portion ofthe cycle. Since the skin is naturally acidic at approximately 5.6 pH,the amplitude of the positive signal would be adjusted upward to providethe pH more compatible with the skin. Of course, the opposite effectcould be obtained, whenever desired, by increasing the amplitude of thenegative portion of the electrical cycle relative to the positiveportion.

It may be desirable to maintain a neutral pH of a drug for drugstability, permeability and irritation control among other reasons. Inmonopolarity DC iontophoretic devices where extremes of acid or alkalineare generated at the electrodes, the drug would quickly reach eitherextreme. Using an AC signal, in accordance with the invention, withsubstantially equal and opposite half cycles, both in amplitude andduration, would, as previously indicated, make the pH at the drugdelivery site essentially neutral. However, there may be circumstanceswhere it is desirable to controllably alter the pH from neutral. Byadjusting the zero reference line, or electrical bias, of theafore-described symmetrical AC signal up or down (by switch), thepositive signal can be increased or decreased in amplitude relative tothe negative signal and vice versa, and, therefore, raise or lower thepH relative to neutral. Ancillary chemicals that are commonly includedin drug formulations, such as buffers and isotonic drugs should bedropped from an iontophoretic drug formulation to further reduceclutter.

Furthermore, it has been discovered that there are instances wheregreater drug concentrations can be delivered by variations in pH fromneutral and increasing the extent of the charged form of the drug to bedelivered.

Modern treatment often demands the simultaneous infusion of differentdrugs. This is known as multi-therapy and is typically performed byinserting two catheters from two different IV units containing differentmedications to treat multiple problems within one patient. With anon-invasive (no catheter) iontophoretic patch, this is easilyaccomplished with the two reservoir system utilized by the simplified,more economical and reliable construction and method of the presentinvention, by placing a different drug into each reservoir. The drugsmay be of the same or opposite polarity. The economy of one unitoffering two distinct treatments is obvious.

In addition, since both electrodes, are “active” with the arrangement ofthe present invention, the system can deliver twice the amount of drugcompared to a comparable DC iontophoretic device. For example, if thedrug to be delivered is positive and the signal in one drug reservoirwere positive at any given instant, then that reservoir will deliver thedrug to the skin. Simultaneously, the other reservoir will be negativeand the same drug will ordinarily not flow. However, if a negative“carrier drug” is made part of the formulation, then this carrier drugwould flow on the negative half of the electrical cycle while pullingalong the desired positively charged active drug. Thus, even though thedesired drug is polarity sensitive, the system of the present inventionwill double the amount of drug delivered. Another embodiment utilizingthe same concept is to employ an amphoteric (dipole) surfactant as partof the drug formulation. Not only does the drug flow continuously, butflow rate efficiency is very substantially enhanced because of thepermeation qualities of the surfactant.

In addition to the foregoing features, the practice of the presentinvention may also include the preparatory process of infusing an ionicsurfactant, either amphoteric or cationic, at the drug delivery site tolower load resistance by increasing permeability and penetration, andthereby enable higher levels of electrical current and drug deliverywith relatively lower driving voltage. This process increases thepermeability of the skin, especially the palms and soles. Electricallydriving in the surfactant at the delivery site is much more effectivethan any presoak or swabbing.

Hence, those concerned with development and use of iontophoretic systemsin the medical field have long recognized the need for a convenient andeffective method and apparatus for preventing skin injury and theformation of vesicles and bulla on the skin in an area subjected to aniontophoretic treatment over extended periods of continuous treatment,which can be physically packaged in a compact and economicalconfiguration, can deliver therapeutic drugs to deeper levels ofpenetration at a high rate and at higher concentrations, without theneed for buffering agents, are capable of delivering large and/or heavymolecular substances, can deliver a plurality of drugs of the same ordifferent polarity simultaneously, and can be used to control pH at thedrug administration site.

These and other objects and advantages of the invention will become morereadily apparent from the following more detailed description of theinvention, when taken in conjunction with the accompanying drawings ofillustrative embodiments.

DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an iontophoretic patch administration deviceconstructed in accordance with the invention, and shown installed uponthe arm of a human subject;

FIG. 2 is an enlarged, perspective view of a presently preferredembodiment of an iontophoretic patch constructed in accordance with theinvention, portions being broken away to illustrate internal structure;

FIG. 3 is a sectional view, taken substantially along the line 3—3 inFIG. 2;

FIG. 4 is a flow chart illustrating a process embodying features of thepresent invention;

FIG. 5 is a flow chart illustrating a more expanded process inaccordance with the invention; and

FIG. 6 is a combined overall block diagram and electrical schematic,including waveforms, of a presently preferred iontophoreticadministration system embodying features of the present invention.

FIGS. 7-8 show circuitry for carrying out the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT(S)

Referring now to the drawings, and more particularly to FIG. 1, there isshown an iontophoretic patch administration device 10, of relativelysimple, economical, reliable and compact construction, embodyingfeatures of the present invention, and shown installed upon the arm 11of a suitable biological subject so that the patch contacts the skin ofthe subject for appropriate administration of therapeutic treatment byiontophoretic delivery of medicaments or the like.

While the device 10 is shown in its presently preferred embodiment as acompact patch, it will be appreciated by those of ordinary skill in theart that a larger structural and/or physical packaging unit (not shown)may be utilized, including a terminal electrode applicator for contactwith the skin, and also embodying various features of the presentinvention.

As best observed in FIGS. 2 and 3 of the drawings, the iontophoreticpatch 10 is a very compact, circular, cylindrical device fabricatedprimarily of an outer plastic shell with internal, preferably integrallymolded, baffles. The plastic shell and baffles are typically molded ofan electrically insulating, flexible vinyl material or the like.

The internal baffles divide the interior of the iontophoretic patch 10(to be marketed under the trademark LECTRO PATCH by General MedicalCompany of Los Angeles, Calif.) into upper and lower, hollow internalchambers 12 and 13, respectively, more specifically, by means of aninterior baffle member 14. The upper chamber 12 contains a compactelectronics package 15, including a suitable microchip and battery powersupply. This upper chamber 12 is electrically insulated from the lowerchamber 13 by the plastic baffle member 14.

The lower chamber 13 contains a pair of iontophoretic electrodes, 16 aand 16 b, typically of electrically conductive silicone/carbon material,and which are separated from each other by an electricallynon-conductive plastic divider baffle 17 forming a separator wall whichdivides the lower compartment 13 into a pair of semi-circular electrodechambers and reservoirs 18 a and 18 b. The chambers 18 a and 18 b housethe electrodes 16 a, 16 b and contain the therapeutic substances to beultimately infused into the biological subject, the drug infusion pathbeing indicated generally by the arrows 20 in FIG. 3.

The iontophoretic electrodes 16 a, 16 b are suitably connectedelectrically into the electronics package 15 via electrically conductivetabs 21 a and 21 b, respectively, extending through appropriate slottedopenings in the chamber dividing baffle member 14. The silicone/carbonelectrodes 16 a, 16 b are typically fabricated of 1-2 ohm per squarecentimeter conductive plastic material. While the electrodes 16 a, 16 bare preferably of silicone/carbon in a presently preferred embodiment ofthe invention, they may be fabricated of other electrically conductive,non-corrosive materials as well. With the AC signal used in the systemof the present invention, there is little or no resistance build-up inthe silicone/carbon electrodes.

The drug reservoirs 18 a and 18 b are filled either with a gelcontaining the therapeutic substances to be administered or a pair offelt pads 22 a and 22 b which have been appropriately saturated with thesubstances to be dispensed.

In addition, an electrical slide switch 24, allowing selection ofdosage, schedule and treatment duration, projects physically, for accessby an operator, through an upper plastic cover plate 26 adhered to thetop of the outer shell of the iontophoretic device 10. The switch 24 iselectrically connected in the chamber 12 to the electronics package 15.The switch 24 may be selectively moved between a “0” (off) position, toeither a “LO” (low current or lower rate of drug delivery) or “HI” (highcurrent or higher rate of drug delivery) switch positions, to eitherturn the device 10 “off” so as to cease electrical operation, or to setthe device for either high or low electric current rate operation whichcan remain in such a state on the patient, continuously if desired, fortypically either 7 days or 10 days, respectively.

The function of the switch 24 in FIG. 1 with markings “0” (meaning off),“LO” and “HI” is as follows:

1) The “0” position keeps the device from functioning. It may also beused to schedule an “off” interval after leaving one of the other drugdelivery positions.

2) The “LO” treatment position infuses the drug at the lowest currentlevel at a continuous, controlled rate. This position can be used fordrugs with a narrow therapeutic index for low level infusion. Anotheruse for this position could be a drug with a long half-life with aschedule of intermittent “0” positions to avoid an accumulation thatmight otherwise result in toxicity.

3) The “HI” treatment position of the switch 24 infuses the drug at acurrent level typically twice as high as the “LO” setting. This positionmay be used to maintain efficacy for drugs with a short half-life, suchas peptides. Also, the “HI” position can be used for a bolus dose comingoff the “LO” position, when therapeutically indicated.

If desired, a second switch (not shown), similar to the slide switch 24,may also be provided and similarly disposed to project through the coverplate 26 of the outer shell of the iontophoretic device 10 and,likewise, be connected to the internal electronics package 15, toselectively vary the frequency of the low frequency duty cycle ofoperation of the iontophoretic patch 10, as where different sizemolecules are to be infused into the patient. In this regard, varyingfrequencies would be used for separation of heavier molecules, such asinsulin and the like, to allow for increased drug transport times duringthe portion of the electrical duty cycle where the particular moleculeis delivered from the drug reservoirs 18 a, 18 b into the skin of thesubject being treated. If desired, the electrical system may bemodified, in a manner well known to those of ordinary skill in the art,to automatically vary the signal frequency periodically.

In addition, a third switch (also not shown) similar to the switch 24may be used, in the manner to be subsequently described in connectionwith the more detailed description of the iontophoretic control systemand circuitry, to vary the ratio of the amplitude of the forward toreverse portions of the overall low frequency AC electrical duty cycle,for purposes of controlling the effective pH at the surface, e.g. theskin, of the patient for a variety of medical reasons.

An LED test indicator 28 extends from the electronics package chamber 13below the cover plate 26, through an appropriate opening in the coverplate, and is observable from the top of the iontophoretic patch 10 toconfirm proper electrical operation of the system for the user. Anadditional switch, such as a membrane switch located inside the patch 10below the cover plate 26, and operable by pressure on the flexible coverplate, (not shown) may be included to selectively connect the indicator28 into and out of the electrical circuit, so as to minimize power drainwhen the indicator is not needed.

Of course, as previously indicated, the invention is not limited tobeing physically packaged as a patch 10. A larger electronics packagemay be housed in a remote instrument containing the electronics package,and either battery or plug-in electrical power may be utilized. A localapplicator would then be electrically connected by cable to the remoteinstrument. The applicator would house suitable iontophoretic electrodesand drug reservoirs akin to the chamber 13 of the patch 10 in FIGS. 1-3.

Referring now to FIG. 4 of the drawings, the overall process whichfacilitates the numerous advantages of the present invention is broadlyillustrated and defined. In this regard, the process calls for the step30 of applying electrical current to a pair of iontophoretic electrodes,such as the electrodes 16 a and 16 b in the iontophoretic patch 10illustrated in FIGS. 1-3. The electrical polarity and, therefore, thedirection of the electrical current flowing from the electrodes andthrough the patient is then, in step 31, periodically reversed (twiceper AC cycle) at low frequencies in the substantially critical range ofapproximately 10 Hz to once every three minutes, or a low frequencylimit of approximately 0.0027 Hz, to achieve the plethora of advantagespreviously and subsequently described herein in connection with thepractice of the present invention. In the practice of the invention,using lidocaine, the system is optimally operated between one cycle perminute and one cycle every six minutes, with one cycle every two minutesbeing typical.

FIG. 5 is a basic block diagram illustrating the invention, wherein anelectrical source 32 is directed to appropriate waveshaping and timingcircuitry 33 for generating the aforedescribed low frequency AC dutycycle which is then directed as electrical current to iontophoreticelectrodes 34 to administer drugs to the patient 11 which is theelectrical load in the system. The system illustrated in FIG. 5 may beimplemented, in a presently preferred embodiment of the invention, bythe more detailed system shown in FIG. 6 of the drawings.

Referring now more particularly to FIG. 6 of the drawings, there isshown a presently preferred embodiment of an overall system forproviding a regulated and periodically reversible electrical currentinto a variable load resistance (the patient), the electrical currentreversing polarity and direction of flow periodically at a very lowfrequency. In the embodiment shown in FIG. 6, a smooth transitionwithout discontinuity in slope, is made between polarities, thusavoiding a shock sensation to the patient when reversing the electricalcurrent. The magnitude and duty cycle of the positive and negativecurrents are substantially the same. The system of FIG. 6 utilizes aconventional DC power supply.

In FIG. 6, the timing of current reversals is determined by anoscillator 40, which produces at its output 41 sharp transitions betweentwo levels, as illustrated by the waveform 42. The electrical output 41is applied to a waveshaping network 43 to produce gradual electricaltransitions, as shown by the output waveform 44 available on line 45.The electrical output of the oscillator 40, and thus the sense of thesmoothed waveform, is reversed when the waveform crosses a predeterminedthreshold 47 determined at junction 46 under the control of a thresholddetection subsystem 50. The voltage waveform 44, less the threshold 47,is applied over line 48 to a suitable voltage-to-current convertersubsystem 49.

The polarity of the electrical current through a floating load 51 (e.g.the patient) reverses at the threshold crossing time, when theinstantaneous electrical load current is zero, as illustrated by thewaveform 52 in FIG. 6. A latch subsystem 53 controls a plurality ofswitches 54 a-54 d, as shown by the waveform 55, to maintain thispolarity until the next threshold crossing, producing smooth transitionsbetween electrical current levels which are, by design, substantiallyequal in magnitude but opposite in sign. The relatively slow rise anddecay evident from leading and trailing edges of the waveform 52provides the desirable electrical ramping up and down of each half cycleto minimize shock sensations.

One example of specific electrical circuitry, suitable for implementingthe system shown in FIG. 6, is set forth in FIG. 7.

With the slow AC signal utilized in the system of the present invention,drug concentration can now be increased substantially beyond two percentwith very important benefits that include enhanced therapeutic value andshortened treatment time. The reason for this is, if, for instance, apositively charged drug is in the drug reservoir when the positive halfof the AC signal is driving that same reservoir, then the positivecomponent of the drug is repelled and driven into the skin. Since alldrug molecules also contain a negative component, that negativecomponent would normally be left behind in the reservoir asnon-productive “clutter”. However, when the AC signal swings negative onthe other half of the signal, the negative component will then also bedriven into the skin, thereby eliminating “clutter” from the reservoir.This “cleansing” of the area, by removal of otherwise deliveryinhibiting “clutter”, enables substantially increased drugconcentrations.

It may be desirable to maintain a neutral pH of a drug for drugstability, permeability and irritation control among other reasons. Inmonopolarity DC iontophoretic devices where extremes of acid or alkalineare generated at the electrodes, the drug would quickly reach eitherextreme. Using an AC signal, in accordance with the invention, withsubstantially equal and opposite half cycles, both in amplitude andduration, would make the pH at the drug delivery site essentiallyneutral. However, as previously indicated, there may be circumstanceswhere it is desirable to controllably alter the pH from neutral. Byadjusting the zero reference line, or electrical bias, of theafore-described symmetrical AC signal up or down (by switch), thepositive signal can be increased or decreased in amplitude relative tothe negative signal and vice versa, and, therefore, raise or lower thepH relative to neutral. Ancillary chemicals that are commonly includedin drug formulations, but should be dropped from an iontophoretic drugformulation, are buffers and isotonic drugs.

Introducing a positive or negative bias into the waveform 52 in FIG. 6consists of adding a separate DC current of appropriate polarity throughthe load 51. This bias current cannot be added directly to thealternating current whose waveform 52 is shown in FIG. 6, because it,too, would then alternate. One example of specific electrical circuitry,suitable for modifying the electrical system shown in FIG. 6 andimplemented by the electrical circuitry of Appendix A, is shown in FIG.8. By shifting the amplitude of the electrical current during oneportion of the duty cycle relative to the other portion of the dutycycle, pH balance is also shifted and this provides an effective methodfor controlling the pH at the drug delivery site in the patient.

In addition, since both electrodes are “active” with the simplifiedarrangement of the present invention, the system can deliver twice theamount of drug compared to a comparable DC iontophoretic device. Forexample, if the drug to be delivered is negative and the signal in onedrug reservoir were negative at any given instant, then that reservoirwill deliver the drug to the skin. Simultaneously, the other reservoirwill be positive and the same drug will ordinarily not flow. However, ifa positive “carrier drug” is included as part of the drug formulation,then this carrier drug would flow on the positive half of the cyclewhile pulling along the desired negatively charged active, drug as well.A typical “carrier drug” would be 4% lidocaine hydrochloride. Hence,even though the desired drug is polarity sensitive, the arrangementdescribed above will double the amount of drug delivered. As willsubsequently be explained herein, the “carrier” medium may also be anionic surfactant, and preferably an amphoteric surfactant.

The iontophoretic electric patch 10 of the present invention is capableof infusing a broad range of drugs up to and including some of the largemolecular peptides. This non-invasive system offers increased efficacywith little or no side effects compared to traditional administrativemethods. Generally, drugs formulated for iontophoretic delivery shouldbe ionized either negatively or positively, free of causing localirritation or a high rate of hypersensitivity, and have an absence ofisotonic and buffer drugs. Used as directed, the iontophoretic patch 10,or the larger version system with a remote applicator, in accordancewith the present invention, produces a systemic result as well as alocalized effect at the point of application.

The presence of hydrochloric acid and sodium hydroxide also has abeneficial value in that these chemicals have a bactericidal effect.Each of these chemicals kill different groups of bacteria. In theconventional DC device, only one chemical is present at one electrodeand, therefore, attacks only a particular group of microbes. With an ACsignal, operating in the critical low frequency range in accordance withthe present invention, the antibacterial effect takes place against thegroups of microbes effected by both polarities, all without damage tothe skin and the drug delivery site.

Another application of the AC signal to sterilize is to send this signaldown conductive catheter tubes. Infection of the wound that the catheterenters is of major concern and a common problem with dialysis users, IVpatients, etc.

As previously suggested, unique features of the iontophoretic patch 10of the present invention include: no tissue damage, rapid onset ofaction, long term dosing at selected levels, compatibility with eitherpolarity drug, capability for delivery of two separate drugs at the sametime (multitherapy) and ability to deliver higher drug concentration.These and other features of the iontophoretic patch 10 greatly enhancedrug therapy. Operating ease comes through the selection switch 24 toprovide programmed input. Selection assures consistent dosing within thegeneral population, thereby maintaining effective plasma concentrations.

The iontophoretic patch 10 of the present invention is capable ofdelivering drugs at a continuous, controlled rate. This allows thephysician/pharmaceutical manufacturer to titrate drug dosage to the mosteffective concentration with minimum or no side effects. Significantlyelevated concentrations can be obtained in 60 minutes or less afterstart of treatment. Thus, a steady-state concentration of the drug canbe maintained during the dosing interval. The physician specifies theduration of application and has a variety of treatment regimens fromwhich to select.

In addition to the treatment regimens previously described, and solelyby way of example and not by way of limitation, other possible regimensmay include: A scheduled switching regimen between “LO” and “HI”positions of the switch 24 for a wide therapeutic index drug, to avoidbuilding a tolerance to a fixed, static level. Another therapeuticopportunity may be where multi-therapy is indicated with drugs ofsimilar half-lives. This application would allow total drug separation(one drug in each of the reservoirs 18 a, 18 b of the patch 10), forinfusion of drugs of the same polarity (alternate delivery) or oppositepolarity (simultaneous delivery). Still another therapeutic variationcould be to halve the infused dosage (intermittent dosing) in the “LO”position of the switch 24 by filling only one reservoir with the drug ofchoice and the other reservoir with common tap water. Conversely, drugdelivery can be doubled if a compatible “carrier” drug of oppositepolarity to the active drug is included in the reservoirs. When thesignal reverses, so as to now block transport of the active drug, theoppositely charged carrier drug would flow with the piggy-backed activedrug.

The iontophoretic patch 10, in accordance with the invention, isdesigned to infuse either positively or negatively charged drugs at aconstant rate, by way of example in connection with a presentlypreferred embodiment of the invention, for up to seven days in the “HI”position of the switch 24 or ten days in the “LO” position. Theclinician fills a hypodermic syringe with approximately 6 cc of theappropriate drug and then proceeds to fully saturate both felt pads 22a, 22 b in each drug reservoir 18 a, 18 b, respectively. Care must betaken to avoid wetting the bottom of the wall 17 separating thereservoirs 18 a, 18 b and that the pads 22 a, 22 b are slightly abovethis separator wall (see FIG. 3) and recessed within the housing beforeapplication to the skin of a patient. Pad fibers must not cross overthis separator wall 17 because they may otherwise cause the device tomalfunction.

Suitable skin preparation must precede iontophoretic patch surfaceadhesion. One possibility is to prepare application areas by swabbingwith approximately fifty percent isopropyl alcohol. At higherconcentrations, permeability is decreased due to the precipitation oftissue proteins.

Iontophoretic treatment should preferably be preceded by a skinpreparation process that strongly enhances permeability. It has longbeen a desire in iontophoretic drug delivery to infuse drugs anywhere onthe human body. Penetrating the palms of the hands or the soles of thefeet is virtually impossible because the skin in these areas is aboutforty times thicker than other areas of the body. Additionally, otherareas of the body, as well as differences in skin resistance amongdifferent human beings, often limits the sites for infusion. This isespecially true when using the low power of an iontophoretic patch 10 ascompared to the relative high power of a full-sized instrument wherefive times or more voltage could be available to overcome high skinresistance. It is, therefore, a great advantage to be able to treat anyarea without having to be selective.

Historically, the art calls for preparing the skin with alcohol, acetoneor surfactants by swabbing the area to be treated with these chemicalsto remove oils and other debris to enhance electrical contact for theiontophoretic applicator. Obviously, these traditional methods of skinpreparation were not satisfactory in overcoming the limits of drugdelivery to many parts of the body. There have also been some efforts toenhance delivery of metallic ions by means of an anionic surfactant, aswell as in vitro experiments to deliver certain drugs using an anionicsurfactant.

In accordance with the invention, it has been discovered that using anappropriate ionic surfactant and driving the surfactant into the skinwith the iontophoretic device (or an equivalent current source), priorto drug delivery, greatly lowers skin resistance and increases skinpermeability thereby allowing treatment to take place anywhere on thehuman body. An alternate arrangement could allow the ionic surf actantto be included in the treatment drug formulation where compatible. Formsof the ionic surfactant can be liquid, gel or equivalent. Suitable ionictype classifications for such surfactants would be cationic andamphoteric. Amphoteric surfactants appear to work best only with an ACsignal, such as that used in the system of the present invention. Withcationic monopolarized surfactants, both AC and DC signals work. In thisregard, the amphoteric surfactant can be the “carrier” medium foranother drug to be delivered.

The use of amphoteric and cationic surfactants, electrically deliveredinto the treatment site, to enhance permeability and penetration at thesite, can be effectively utilized as a skin preparation technique forboth iontophoretic and non-iontophoretic drug delivery at that site.

In the practice of the present invention, it has been discovered thatamphoteric surfactants performed much more efficiently than cationicsurfactants, while cationic surfactants were considerably more effectivethan anionic surfactants such as sodium lauryl sulfate. Suitableexamples of such surfactants successfully utilized in the practice ofthe invention are:

SURFACTANT PREPARATION SOLUTIONS (1) AMPHOTERIC Product Name:AMPHOTERIC-L Chemical Name: COCO AMIDOPROPYL BETAINE Physical ClearLiquid Appearance: Manufacturer: Exxon Chemical Company PerformanceProducts Group Tomah Products 1012 Terra Drive (P.O. Box 388) Milton,Wisconsin 53563 (2) CATIONIC Product Name: DEHYQUART A Chemical Name:CETYL TRIMETHYL AMMONIUM CHLORIDE Physical Clear Liquid Appearance:Manufacturer: Henkel Corporation Chemical Specialties Division 300Brookside Avenue Ambler, Pennsylvania 19002

Surfactants may include suitable functional materials such as couplingagents, antimicrobials, chelating agents and the like.

Of course, it will be appreciated that the aforementioned ionicsurfactants are presented only by way of example, and those of ordinaryskill in the art may substitute other amphoteric or cationicsurfactants, currently known or unknown, without departing from thespirit and scope of the invention.

The vastly increased permeability and penetration capability at thetreatment site, made possible by use of an appropriate ionic surfactant,and particularly an amphoteric surfactant, yields yet another embodimentof the invention relating to sweat control by iontophoresis. In thisregard, sacrificial aluminum electrodes may be substituted for thesilicone/carbon electrodes 16 a, 16 b, to direct ions into the eccrineduct for sweat control. The aluminum ions precipitate the skin proteintherefore causing a plug that lasts weeks (no sweat period). Thetreatment site is either first prepared using an appropriate surfactant,as outlined above. Thereafter, tap water is placed in the reservoirs 18a, 18 b. Alternatively, an appropriate ionic, and preferably amphoteric,surfactant is placed into the reservoirs 18 a, 18 b adjacent thealuminum electrodes for delivery into the treatment site.

As previously indicated, in order to maximize electrical current flow iniontophoretic devices, generally the tradition in the prior art has beento increase the electrical power output of the device and limit the drugconcentration to around 2% because it was believed that greaterconcentrations would actually impede the amount of drug delivered.However, in addition to the previous discussions for achieving higherdrug concentrations in accordance with the practice of the invention,greater drug concentrations can be optimized and made even moreeffective by two additional considerations. These considerations are pHand the extent of the charged form of the drug to be delivered. By wayof example, lidocaine at a pH of 7.0 with a given drug concentration mayhave only a satisfactory current flow. The charge for lidocaine at a pHof 7.0 is less than 50%. In further experiments, the pH of the lidocainewas adjusted in a conventional manner to approximately 6.8 where atleast 90% of the drug was in charged form and an approximate 30 to 40%increase in current at the same level of drug concentration wasobserved. Hence, the pH should be near neutral and the exact selectionof pH should be dependent on the specific drug being in maximum chargedform. The vast increase in flux at this optimized version allowed stillgreater drug concentrations that almost immediately broke down skinbarriers upon application. This greatly lowered resistance andeliminated the need for penetration enhancers as the skin preparationprelude to a drug treatment.

In general, placement for systemic infusion is the volar surface of theforearm near the elbow. If the use is to treat a lesion or any otherspecific site, the patch 10 should be placed over that site for targetdelivery. If the application site is contoured, the iontophoretic patch10 may be bent to conform with this irregular surface. The bend shouldtake place in line with the separation wall 17 running down the centerof the patch 10.

In normal operation, the switch 24 is moved from the “0” position toeither “LO” or “HI” as prescribed. The user may feel a-gentle tingle foronly the first approximately thirty seconds to one hour (priming period)of treatment, depending to some extent upon the permeability at thedelivery site. Treatment is then continued for the prescribed period oftime. The patch 10 is switched to the “0” position when not in use.

After completion of treatment, the iontophoretic patch 10 shouldnormally be discarded. The hands and drug application site should bewashed with soap and water and then dried to remove any remnant drug.

In normal use, after the patch 10 has been applied and working forapproximately one hour, the following procedures can be used throughoutthe seven day (“HI”) or ten day (“LO”) treatment to prove workability.If the green indicator 28 lights when switched into the electricalcircuitry (in accordance with the circuitry of FIG. 7), it means thebatteries are fresh and the device is delivering the medication. If theindicator 28 fails to light, it means that the batteries are dead andthe device must be replaced. If the green indicator 28 flashes on andoff continuously, it can mean one of the following malfunctions: a) thatthe drug is leaking from one side of the separation wall 17 to the other(oversaturation of pads), b) that the drug level is too low and moremust be added to the felt pad 18 a or 18 b, or that the patch 10 itselfis not firmly adhered to the skin surface (especially a contouredsurface) and c) (for investigators) that an unproven formulation isnon-ionic or of such poor conductivity that minimum current needs forthe “LO” position (approximately 0.5 ma by way of example) or the “HI”position (approximately 1.0 ma by way of example) cannot be met. Underthese conditions, the investigator may consider adding another drug toact as a “carrier” for the substantially non-ionic drug. Electroosmotictransport of water or solvent also enhances penetration ofnon-electrolytes.

It will be apparent that the various electrical subsystems indicated inFIGS. 5 and 6 of the drawings can be implemented readily by those ofordinary skill in the art without the exercise of inventive skill.

Hence, those concerned with development and use of iontophoretic systemsin the medical field have long recognized the need for a convenient andeffective apparatus and method for preventing iontophoretic burns andirritation and the formation of vesicles and bulla on the skin in anarea subjected to an iontophoretic treatment over extended periods ofcontinuous treatment, which can be physically packaged in a simple,reliable, relatively inexpensive and compact configuration, can increasepermeability and penetration at the treatment site, can delivertherapeutic drugs at a high rate and at higher concentrations, withoutthe need for buffering agents, are capable of delivering large molecularsubstances, can deliver a plurality of drugs of the same or differentpolarity simultaneously, and can be used to control pH at the drugadministration site.

Accordingly, it will be apparent from the foregoing that, whileparticular forms of the invention have been illustrated and described,various modifications can be made without departing from the spirit andscope of the invention. Therefore, it is not intended that the inventionbe limited, except as by the appended claims.

I claim:
 1. A system for applying iontophoretic treatment to a biological subject, said system comprising: a reservoir for holding a substance electrode means for directing an electrical current through a portion of said subject in a first direction for delivery of a substance to said subject; and means for intermittently reversing the direction of said electrical current at a relatively low frequency which prevents skin damage, between approximately 20 times per second and approximately once every three minutes, whereby iontophoretic treatment may be continuous for extended periods of time, said means having at least one setting wherein said forward current delivery and reverse current delivery are of substantially equal magnitude and duration.
 2. A system as set forth in claim 1, and further comprising: means for selectively varying the frequency of the electrical current to accommodate the transport times of different size molecules.
 3. A combination as set forth in claim 1, and further including: means for selectively varying the amplitude of the electrical current in one direction relative to the amplitude of the electrical current in the opposite direction to vary a PH in the reservoir, said pH being selected to optimize transport of said substance.
 4. In an iontophoretic system for infusion of medical substances into a biological subject, the combination comprising: electrically conductive electrode means adapted to be located adjacent a surface of said subject to be treated; a drug storage reservoir adjacent said electrode means and adapted to receive at least one medical substance between said electrode means and said surface of said subject to be treated; means for conducting an electrical current through said surface of said subject in a first direction through said electrode means on said subject to deliver said medical substance to said subject; and means for periodically and regularly reversing the polarity of said electrode means to cause said electrical current to flow in a second direction opposite to said first direction, at a relatively low frequency which prevents skin damage to said subject and simultaneously provides adequate molecular transport time for said drug to be delivered into said surface of said subject, whereby drug infusion may be continuous for extended periods of time, said means having at least one setting wherein said forward current delivery and reverse current delivery are of substantially equal magnitude and duration.
 5. A method of applying iontophoretic treatment to a biological subject, said method including the steps of: conducting an electrical current through a surface of said subject in a first direction to an electrode located at the surface on said subject to deliver a substance to said subject; and intermittently reversing, at a relatively low frequency which prevents skin damage, between approximately 20 times per second and approximately once every three minutes, the polarity of said electrode to cause said electrical current to flow in a second direction opposite to said first direction, wherein said current flow in said first and second directions are substantially of equal magnitude and duration whereby iontophoretic treatment is continued for an extended period of time to deliver said substance.
 6. A method as set forth in claim 5, including the step of: selectively varying the frequency of the electrical current to accommodate the transport times of different size molecules.
 7. A method of iontophoretic infusion of substances into a biological subject, comprising the steps of: locating an electrically conductive electrode adjacent to a surface of said subject to be treated; placing at least one substance at said electrode at said surface of said subject to be treated; conducting an electrical current through said surface of said subject in a first direction from said electrode to deliver said substance to said subject; and reversing at a relatively low frequency, between approximately 20 times per second and approximately once every three minutes, the polarity of said electrode to cause said electrical current to flow in a second direction opposite to said first direction, wherein said current flow in said first and second directions are of substantially equal magnitude and duration whereby skin damage to said subject is avoided and drug infusion is continued for an extended period of time to deliver said drug.
 8. A method as set forth in claim 7, including the step of: selectively varying the frequency of the electrical current to accommodate the transport times of different size molecules.
 9. A method of iontophoretic infusion of substances into a biological subject, comprising the steps of: locating an electrically conductive electrode upon said subject to be treated; placing at least one substance between said electrode and a surface of said subject to be treated; conducting an electrical current through said surface of said subject in a first direction from said electrode to deliver said substance to said subject; and reversing the polarity of said electrode to cause said current to flow in a second direction opposite to said first direction, at a relatively low frequency which prevents skin damage to said subject and simultaneously provides adequate molecular transport time for said substance to be delivered into said surface of said subject, wherein said current flow in said first and second directions are of substantially equal magnitude and duration whereby infusion of said substance is continued for an extended period of time and wherein the polarity reversal occurs after the accumulated time periods of actual substantial electrical current flow in either direction equal a selected period of time between approximately 0.05 seconds and approximately 3 minutes. 